10, 11-dihydro-5-hydroxy-5-vinyl-5h-dibenzo-[a, d] cycloheptenes



United States Patent 3,354,206 10,11 EHYDRO-5-HYDROXY-5-VINYL-5H-DIBENZO-[a,d}YCLOHEPTENES Norman L. Wendier, Summit, and Robert D.Hoiisommer, In, and David Taub, Metuehen, N.J., assignors to Merci: &(30., Inc., Rahway, N.J., a corporation of New Jersey No Drawing.Continuation of application Ser. No. 318,165, Get. 23, 1963. Thisapplication Apr. 26, 1967, Ser. No. 634,439

17 Claims. (Cl. 260-556) ABSTRACT OF THE DECLGSURE The invention isdirected to 10,1l-dihydro-5-hydroxy-S-Vinyl-SH-dibenzo[a,d]cycloheptenes and their unsaturated form whichare intermediates in the preparation of anti-depressants andtranquilizers.

This application is a continuation of application Serial No. 318,165,filed October 23, 1963, now abandoned.

This invention relates to the preparation of compounds which are usefulas intermediates in the preparation of dibenzocycloheptenes. Inparticular, the invention relates to a method for the preparation of5-cyclopropyl-5-hydroxy derivatives of dibenzocycloheptenes which, inturn, may be readily converted to 5H-dibenzo[a,d]cycloheptenes and10,1l-dihydro-SH-dibenzo[a,d]cycloheptenes which are substituted at the5-position with a tertiary aminopropylideue radical. These lattercompounds are useful in the field of mental health in that they areactive as anti-depressants and/ or tranquilizers.

In accordance with the process of the present invention, adibenzocyclohepten-5-one is reacted with a Grignard reagent derived froma vinyl halide and the resulting Grignard adduct hydrolyzed to form the5-l1ydroxy-S-vinyldibenzocycloheptene derivative. The latter vinylcarbinol is then treated with methylene iodide in the presence of acopper-zinc couple. This process may be illustrated as follows:

K5 W U (2) Hydrolysis (Step I) CH I Cu-Zn (Step II) Patented Nov. 21,167

tetraiydrofuran Mg HalCH=CH2 HalMgCH=CH2 It has been found that the useof tetrahydrofuran as the solvent for the reaction results in rapidproduction of the Grignard reagent in high yield,

The reaction of the ketone with the Grignard reagent (Step I) isinitially carried out at temperatures below 50 C., and preferably in therange of 40 to 50 C. Higher temperatures may be utilized with cautionand temperatures below 40 C. may also be employed providing that thetemperature is not too low so as to cause precipitation of the Grignardreagent. The temperature may be adjusted by the use of an ice-bath or bycontrolling the rate of addition of one of the reactants to the mixture.The reaction is preferably carried out in a solvent and it has beenfound that tetrahydrofuran is excellent for this purpose. Accordingly,the ketone may be added directly to the reaction mixture in which theGrignard reagent is prepared. However, any inert, organic solvent may beutilized. Hydrolysis of the resulting Grignard adduct is carried out insuch a way that strongly acidic conditions are avoided. Hydrolysis canbe conveniently effected with a saturated ammonium chloride solution,although water alone may be sufficient.

In Step II of the process, the vinyl carbinol is reacted with methyleneiodide in the presence of a zinccopper couple. In carrying out thisreaction, it is preferred to employ a substantially anhydrous, inertorganic solvent. Suitable solvents include ethers such as ethyl ether,tetrahydrofuran and the like. The temperature at which the reaction isrun is not critical. Preferably, the reaction is carried out at thereflux temperature of the system. The product is readily recovered inconventional manner.

The ketones employed in the above process may be readily preparedfollowing the procedure described in the literature or in the exampleshereinbelow. The conversion of the 5 hydroxy-5-cyclopropyl derivativesof dibenzocycloheptenes prepared by the process of this invention to thecorresponding dibenzocycloheptenes which are substituted at the5-position with a tertiary aminopropylidene radical, may be accomplishedutilizing the process described by R. D. Hotfsommer, D. Taub and N. L.Wendler in the J. Org. Chem, 27, 4134 (1962).

The process of the present invention is more fully described in thefollowing examples. It is to be understood, however, that the examplesare illustrative only and are not to be construed as limiting theinvention.

A ml. 3-necked flask with stirrer, Dry Ice'acetone condenser withnitrogen inlet, and addition funnel is charged with 1.17 g. (48millimoles) of magnesium turnings. The system is flamed-out with a heatgun and cooled under dry nitrogen. The magnesium metal is covered with10 ml. of dry tetrahydrofuran (TI-IF) and 2-3 ml. of a solution of 5.25g. (49 millimoles) of vinyl bromide in 10 ml. of THF is added. Thereaction mixture is warmed slightly until reaction begins, after whichthe vinyl bromide solution is added dropwise, with stirring, at such arate as to maintain a temperature of 5060 C. The addition is complete in15 minutes, after which the reaction mixture is stirred under gentlereflux until all of the magnesium is consumed (2 hours). A solution of5.0

d g. (24 millimoles) of 10,1l-dihydro-SH-dibenzo[a,dJcyclohepten-S-onein 25 m1. of THF is added, with stirring, to the Warm reaction mixtureat a rate suflicient to maintain a temperature of 4050 C. The additionis complete in 25 minutes, accompanied by considerable darkening of thereaction mixture. Stirring and heating (50 C.) are continued for 1 hour.At the end of this time a thin-layer chromatographic probe indicatesthat the reaction is complete. The reaction mixture is chilled in anice-bath and treated, dropwise, with 25 ml. of saturated ammoniumchloride solution. The aqueous layer is extracted with two 15 ml.portions of ether and the combined ether-THF solutions are washed with15 ml. of saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and taken to dryness in vacuo to yield 5.90 g. ofyellow oil which exhibits the following properties:

xggf 2.70, 2.37, 6.18, 6.75, 6.9, 7.13, 7.62, 7.9, 8.63,

9.0, 9.48, 9.83 and 10.35

Example 2.5-cyclopr0pyl-10,1I -dihydr-5-hydr0xy-5H- dibenzo [a,d] cycloheptene A 50 ml. B-necked flask fitted with a stirrer, condenser bank,and addition funnel is purged with dry nitrogen and charged with 1.53 g.of the copper-zinc couple (prepared by the procedure of R. S. Shank andH. Shechter, J. Org. Chem., 24, 1825 [1959]), 15 ml. of dry ethyl ether,and two crystals of iodine. Methylene iodide (4.90 g., 18.3 millimoles)is added and the reaction mixture warmed to a gentle reflux which ismaintained for 30 minutes. The reaction mixture is then cooled slightlyand 2.00 g. (8.46 millimoles) of 10,11dihydro--hydroxy-5-vinyl-5H-dibenzo[a,d] cycloheptene in 5 ml. of dryethyl ether added slowly, with stirring, over 25 minutes. The reactionmixture is then stirred and refluxed for 2% hours. The reaction mixtureis cooled to room temperature and treated with ml. of saturated ammoniumchloride solution. The aqueous layer is extracted with two portions ofether and the combined ether solutions washed with two 15 ml. portionsof saturated potassium carbonate solution, 15 ml. of saturated sodiumchloride solution, dried over anhydrous magnesium sulfate andconcentrated in vacuo to 2.26 g. of yellow oil. The crude oil isre-dissolved in ether, treated with charcoal, filtered through Celite,and the ether replaced with hexane While concentrating to small volume.Seeding the solution with a crystal of authentic 10,11 dihydro 5 hydroxy5 cyclopropyl 5H dibenzo[a,d]cycloheptene yields 660 mg. of crystallineproduct with a M.P., 6869.5 C. The authentic sample had a M.P., 69-71 C.A mixture of the product crystals and authentic sample did not depressthe M.P., 6871 C. An additional 450 mg. of cyclopropyl carbinol isobtained by chromatography of the mother liquor to aflord a total yieldof 52% over the two steps.

Example 3.-3 methylmercapto 5H dibenz0[a,d]cyclohepten-S-one Step A.Preparation of cuprous methylmercaptide. Concentrated ammonium hydroxidesolution, 300 ml., is placed in a 1 liter, 3-necked flask fitted with astirrer and gas inlet tube. The apparatus is cooled in an ice-bath andflushed with dry nitrogen while 40.0 g. (0.40 mole) of cuprous chlorideis added portionwise with stirring. To the dark blue solution is added95% ethanol, 300 ml., and then methylmercaptan is bubbled into thecooled solution until precipitation is complete and the supernatantsolution becomes yellow. The solid is collected and washed bycentrifugation with four portions of dilute ammonium hydroxide solution,followed by four portions of absolute ethanol. The yell-ow product isdried under reduced pressure at 45 50 C. and finally in a vacuum e icctor over 4 concentrated sulfuric acid. The yield of product is 41.4 g.(93%).

Ste B. Preparation of 3-methylm'ercapto-5H-dibenz0 [a,d1cycl0hepten 5one.3 bromo 5H dibenzo- [a,d]cyclohepten 5 one, 7.93 g. (0.028 mole),and cuprous methylrnercaptide, 4.01 g. (0.036 mole), prepared asdescribed in Step A, are put in a ml. flask fitted with a stirrer andreflux condenser. Quinoline, 44.8 ml., and pyridine, 4.0 ml., are addedand the slurry is heated at 200 C. with stirring for six hours. Thereaction mixture is poured into 6 N hydrochloric acid, ml., and ice, andextracted with five m1. portions of boiling benzene. The combinedextracts are washed with three 200 ml. portions of 3 N hydrochloricacid. After washing with water, the solvent is evaporated under reducedpressure leaving a brown oil, weight 7.41 g., as residue. The oil isdissolved in absolute methanol, 125 ml., and boiled with 370 mg.decolorizing carbon for thirty minutes. The filtrate is concentrated to60 ml. and a yellow solid separates, along with a brown oil. The solidis mechanically separated from the oil and dried in a Vacuum desiccatorover concentrated sulfuric acid. The product weighs 2.77 g. and melts at66.5-67.5 C. The brown oil is evaporatively distilled at 146 C./0.1 mm.and the sublimate is crystallized from 25 ml. of absolute methanol togive 2.65 g. of material melting at 66.5-67.5 C. (77% yield).

AnaZysis.-Calcd. for C H OS: C, 76.16; H, 4.80; S, 12.71. Found: C,76.35; H, 4.61; S, 12.60.

Example 4 .1 0,11 -dihydro-3-methylmercapto-5H- di b enzo [a,d cyclohepten-S-one Following the procedure of Example 3, Step B, and employingan equivalent amount of3-brorno-l0,l1-dihydro-SH-dibenzo[a,d]cyclohepten-5-one in place of3-bromo-5H-dibenzo[a,d]cyclohepten-5-one, there is obtained 10,11dihydro-3-methylmercapto-SH-dibenzo[a,d] cyclo hepten-S-one.

Example 5.3-methylsuZf0nyl-5H-dibenz0[a,d]cycloheplen-S-one 3methylmercapto-SH-dibenzo[a,d]cyclohepten-5-one (10.70 g., 0.042 mole)is dissolved in 35 ml. of glacial acetic acid. Hydrogen peroxide (30%,15 ml.) is added and the solution is stirred at room temperature for 65hours. The white solid that precipitates is collected and dried to yield10.81 g. (91%) of product melting at 158- 159 C. An analytical samplefrom a previous experiment melts at 157.5 C. after recrystallizationfrom 95% ethanol.

AnaZysis.Calcd. for C l-1 0 5: C, 67.59; H, 4.26; s, 11.23. Found: c,67.62; H, 4.25; s, 11.41.

Example 6.10,II-dihydro-S-merhylsulfonyl fl-ldibenz0[a,d]cycl0hepten-5-one Following the procedure of Example 5, and employing anequivalent amount of10,11-dihydro-3-methylmercapto-5H-dibenzo[a,d]cyclohepten-S-one in placeof 3-methylmercapto-SH-dibenzo[a,d]cyclohepten-S-one, there is obtained10,1 1-dihydro-3 -methylsulfonyl-5H-dibenzo a,d] cyclohepten-S-one.

Example 7.10,II-dilzydr0-3-dim'ethylsulfamoyl-SH- di benzo [a,dcyclolzeptei1-5 -one Step A.7-br0m0-3-flrtor0sulf0nyl-10,11-dihydr0-5H-dibenzo[a,d]cyclohepten-5-one.-Fluorosulfonicacid, 100 ml., is placed in a 300 ml. 3-necked round bottom flaskequipped with polyethylene inlet tube and polyethylene exit tube withdrying tube half-filled with anhydrous sodium fluoride. A nitrogenatmosphere is maintained throughout the reaction. With stirring, 17.0 g.(0.059 mole) of 3-bromo-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S-oneis added in portions over 20 minutes. After stirring another 10 minutes,the dark green solution is heated on the steam-bath for 6 /2 hours. Themixture then is cooled to room temperature, poured cautiously withstirring into 1.5 k of crushed ice, and allowed to stand overnight atroom temperature. The brown solid is collected, washed with water, driedin a vacuum desiccator over sodium hydroxide, and then extracted in aSohxlet extractor with 700 ml. of boiling cyclohexane for 16 hours. Oncooling, the cyclohexane extract deposits 11.65 g. (53%) of7-bromo-3-fiuorosulfonyl-l0,ll-dihydro-SH- dibenzo[a,d]cyclohepten-S-oneas dark yellow flakes, M.P. 148-151 C. Recrystallizations from ether andcyclohexane give an analytical sample, M.P. 150152 C.

i lnalysis.Calcd. for C H O FBrS: C, 48.79; H, 2.73; S, 8.69. Found: C,48.78; H, 2.83; S, 8.87.

Step B. 7 bromo-J0,11-dihydr-3-dimelhylsulfamoyl- Sid-dibenzo[a,d]cycl0lzepten-5-0ne.7 bromo-l0,11-dihydro 3 fiuorosulfonyl 5Hdibenzo[a,d] cyclohepten- 5-one (2.5 g., 0.00677 mole) together with 30ml. of 25% aqueous dirnethylamino and 30 ml. of pdioxane is heated torefluxing for 3 hours. The brown solution is evaporated to dryness underreduce pressure and the residue partitioned between benzene and water.After washing with Water, the benzene layer is evaporated to drynessunder reduced pressure, leaving 7-bromo-10,11-dihydro3-dimethylsulfamoyl-5H dibenzo [a,d]cyclohepten-5-oneas a tan solid, M.P. 142145 C., in a yield of 2.1 g. (80%). Ananalytical sample melts at 146-148 C. after crystallizations frommixtures of benzene and hexane and from methanol.

Analysis.-Calc-d. for C HmOgNBI'SZ C, 51.78; H, 4.09; N, 3.55. Found: C,51.71; H, 4.12; N, 3.53.

S rep C.10,11-dilzydro-5-dimethylsulfam0yl-5H-dibenzo-[a,d]Cyc1012epten-5-one.7-bromo10,11dihydro-3- dirnethylsuliamoyl-SH-dibenzo[a,d]cyclohepten 5 one, 8.0g. (0.0203 mole), is dissolved in a mixture of 100 ml. of absoluteethanol, 70 ml. of dimethylformamide, and 5 ml. of triethylamine. Thesolution is hydrogenated at atmospheric pressure and in the presence of600 mg. of 10% palladium on charcoal catalyst until hydrogen uptake iscomplete. Catalyst is removed by filtration and Washed with absoluteethanol. The filtrate is evaporated to dryness under reduced pressureand the residue triturated with benzene. The insoluble triethylaminehydrobromide is filtered and the benzene filtrate evaporated to drynessunder reduced pressure. Crystallization of the residual white solid fromabsolute ethanol affords 6.1 g. (97%) of10,1l-dihydro-3-dimethylsulfamoyl-SH-dibenzo[a,d]cyclohepten-5-one, M.P.122124 C. The melting point is unchanged after crystallization fromabsolute ethanol.

Aizalysis.-Calcd. for C I-I O NS: C, 64.74; H, 5.44; N, 4.44. Found: C,64.20; H, 5.47; N, 4.16.

Example 8.3-dimezlzylsrrlfam0y I-SH-dibenzo [L1,d] cycloh epten-S-one Amixture of 10,11 dihydro-3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten5-one (6.1 g., 0.0194 mole), N brornosuccinimide(3.6 g., 0.029 mole), benz-oyl peroxide (50 mg), and 50 ml. of benzeneis stirred and heated to refluxing for 3 hours. The precipitatedsuccinimide is filtered and washed with warm benzene. After washing with5% aqueous sodium hydroxide and then with water, the benzene filtrate isevaporated to dryness under reduced pressure. The residual oily solid issuspended in 75 ml. of triethylamine and the mixture stirred at refluxfor 16 hours. Triethylamine is evaporated under reduced pressure and theresidual solid partitioned between benzene and water. The benzene layeris separated, washed with 3 N hydrochloric acid and then with water, andevaporated to dryness under reduced pressure. Crystallization of theresidual solid from 95% ethanol gives 2.83 g. (46.5%) of 3dimethylsulfamoyl-SH-dibenzo[a,d]cyclohepten-S- one, M.P. 129.5135.5 C.An analytical sample melts at 138.5-1395" C. after repeatedcrystallizations from 95 ethanol.

Analysis.Calcd. for C H O NS: C, 65.16; H, 4.83; N, 4.47. Found: C,64.88; H, 4.85; N, 4.11.

10,11-dihydro-3-methylsultonyl- Example 9 Ketone Product5-hydroxy-3-methylmercapto-5- viny1-5H-dibenzo[a,d]cycloheptene.

10,11:dihydro-hydroxy-3-methylmercapto-dvinyl-EvH-dibenzo-3-methylmercapto-5H-dibenzo- [a,d]cycl0hepten-5-one.

Example 10 Following the procedure of Example 2 and employing anequivalent amount of the vinyl carbinol designated below in place of10,11-dihydro-5-hydroxy-5-vinyl-5H- dibenzo[a,d] cycloheptene, there isobtained the products enumerated below.

Vinyl Carbinol Product We claim:

1. A compound of the formulae:

HO CH=CH2 CH=CH2 wherein X is hydrogen, halogen, loweralkoxyloweralkylsulfonyl or diloweralkylsulfamoyl.

2. A compound of the formula:

HO CH=CH1 wherein X is hydrogen, halogen, loweralkoxy,loweralkylsulfonyl or diloweralkylsulfamoyl. 3. A compound of theformula:

wherein X is hydrogen, halogen, loweralkoxy, loweralkylsulfonyl ordiloweralkylsulfamoyl.

4. The compound of claim 1 wherein X is halogen.

5. The compound of claim 1 wherein X is lower-alkylsulfonyl.

9. 5-hydroXy-3-methylsulfonyl-S-Vinyl-SH-dibeuzo[a,d]'

cycloheptene.

10. 10,11 dihydro 5 hydroxy-3-methy1sulfonyl-5- vinyl-SH-dibenzo [a,d]cycloheptene.

11. 3 chloro 10,11 dihydro-S-hydroxy-S-vinyl-5H- dibenzo [a,d]cycloheptene.

12. 5 hydroxy 3 methoxy-S-vinyl-5H-dibenzo[a,d] cycloheptene.

13. 3 dimethylsulfamoyl 5 hydroxy-S-vinyl-SH- dibenzo [a,d]cycloheptene.

14. 10,11 dihydro 3 dimethylsulfamoyl-S-hydroxy- 5 -vir1yl-5 H-dibenz0[a,d] cycloheptene.

15. 5 hydroxy 3 methylmercapto-5-yiny1-5H-dibenzo[a,d]cycloheptene.

16. 10,11 dihydro 5 hydroxy-3-methylmercapto-5- vinyl-SH-dibenzo [a,d]cycloheptene.

17. 10,11 dihydro 5 hydroXy-3-methoXy-5-vinyl- SH-dibenzo [a,d]cycloheptene.

References Cited Hoffsommer et 211., J. Org. Chem., v0l. 27, pp. 4134-4137 (1962).

Hofisomrner et al., J. Org. Chem., v01. 28, p. 1752 (July 1963).

JOHN D. RANDOLPH, Primary Examiner.

HARRY I. MOATZ, Assistant Examiner.

1. A COMPOUND OF THE FORMULAE: 